Plasma Biomarkers Reflecting Profibrotic Processes in Heart Failure With a Preserved Ejection Fraction: Data From the Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection Fraction Study

Abstract

Background: Heart failure with preserved ejection fraction is a clinical syndrome that has been associated with changes in the extracellular matrix. The purpose of this study was to determine whether profibrotic biomarkers accurately reflect the presence and severity of disease and underlying pathophysiology and modify response to therapy in patients with heart failure with preserved ejection fraction.

Methods and results: Four biomarkers, soluble form of ST2 (an interleukin-1 receptor family member), galectin-3, matrix metalloproteinase-2, and collagen III N-terminal propeptide were measured in the Prospective Comparison of ARNI With ARB on Management of Heart Failure With Preserved Ejection Fraction (PARAMOUNT) trial at baseline, 12 and 36 weeks after randomization to valsartan or LCZ696. We examined the relationship between baseline biomarkers, demographic and echocardiographic characteristics, change in primary (change in N-terminal pro B-type natriuretic peptide) and secondary (change in left atrial volume) end points. The median (interquartile range) value for soluble form of ST2 (33 [24.6-48.1] ng/mL) and galectin 3 (17.8 [14.1-22.8] ng/mL) were higher, and for matrix metalloproteinase-2 (188 [155.5-230.6] ng/mL) lower, than in previously published referent controls; collagen III N-terminal propeptide (5.6 [4.3-6.9] ng/mL) was similar to referent control values. All 4 biomarkers correlated with severity of disease as indicated by N-terminal pro B-type natriuretic peptide, E/E', and left atrial volume. Baseline biomarkers did not modify the response to LCZ696 for lowering N-terminal pro B-type natriuretic peptide; however, left atrial volume reduction varied by baseline level of soluble form of ST2 and galectin 3; patients with values less than the observed median (<33 ng/mL soluble form of ST2 and <17.8 ng/mL galectin 3) had reduction in left atrial volume, those above median did not. Although LCZ696 reduced N-terminal pro B-type natriuretic peptide, levels of the other 4 biomarkers were not affected over time.

Conclusions: In patients with heart failure with preserved ejection fraction, biomarkers that reflect collagen homeostasis correlated with the presence and severity of disease and underlying pathophysiology, and may modify the structural response to treatment.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00887588.

Keywords: biomarkers; extracellular matrix; heart failure; homeostasis; pathophysiology.

Figure 1

A, Relationship between ln(sST-2) and ln(NT-proBNP) in patients with heart failure with a preserved ejection fraction; Spearman correlation r=0.19, P=0.002. B, Relationship between ln(sST2) and left atrial volume (LAV) in patients with heart failure with a preserved ejection fraction; correlation r=0.25, P=0.002. C, Relationship between ln(sST2) and ln(Gal-3) in patients with heart failure with a preserved ejection fraction; correlation r=0.23, P<0.0001. ; Gal-3 indicates galectin 3; NT-proBNP, N-terminal pro B-type natriuretic peptide; and sST-2, soluble suppressor of tumorigenicity-2.

Figure 2

Change from baseline in left atrial volume (LAV) produced by treatment with LCZ696 vs valsartan in those with a baseline value of soluble form of ST2 (sST-2) and galectin 3 (Gal-3) above and below the median. When patients were divided into 2 groups, above and below the baseline median value of sST-2 or Gal-3, the effect on change in LA volume produced LCZ696 vs valsartan differed; in patients with a baseline value of sST-2 or Gal-3 above the median, treatment with LCZ696 did not result in a significant change in LA volume; in patients with a baseline value of sST-2 or Gal-3 below the median, treatment with LCZ696 resulted in a decrease in LA volume after 36 weeks of treatment compared with baseline.

Figure 3

Schematic representation of mechanisms suggested by changes in circulating biomarkers. Increased galectin 3 (gal-3) secreted by mast cells may contribute to transdifferentiation of fibroblasts to myofibroblasts. Increased soluble form of ST2 (sST-2) may contribute to ST-2 profibrotic signaling. Decreased matrix metalloproteinase-2 (MMP-2) may contribute to less collagen degradation. In aggregate, these changes may contribute to increased myocardial extracellular matrix (ECM) collagen and fibrosis and may be reflected by the changes measured in circulating biomarkers. HFpEF indicates heart failure with preserved ejection fraction; and IL, interleukin.